Recent results from large phase II/III clinical trials on adenoviral-mediated VEGF delivery have been inconclusive if not disappointing so far. We believe a sounder strategy may be to take advantage of the HIF-1 upstream transcriptional regulator that can activate several downstream genes such as VEGF, FGF, IGF, angiopoietin, and erythropoietin. However, HIF-1 has a short biological half-life due to endogenous degradation by prolyl hydroxylase-2 (PHD2). Therefore, we hypothesize that short hairpin inhibition of PHD2 (shPHD2) represent a novel approach to induce therapeutic angiogensis. On the flip side, persistent and unregulated angiogenesis can lead to hemangioma in the heart and thus controlling gene expression in a targeted and regulatory fashion is needed. Another priority is to develop novel techniques that can be used to track gene expression in living subjects noninivasively, longitudinally, and quantitatively. Thus, the primary goal of this R01 proposal is to use our multi-disciplinary expertise in vector design, molecular imaging, vascular biology, and translational models to address the above questions. Our specific aims are to (1) develop smart vectors with robust and prolonged transgene expression, (2) monitor the pharmacokinetics and biodistribution of our novel vector in vivo, (3) demonstrate mechanisms of shPHD2 mediated gene therapy for myocardial ischemia, and (4) evaluate the safety, efficacy, and optimal delivery conditions in translational models. At the end of 5 years, we hope to translate these findings to treatment of coronary artery disease patients with our novel smart vector systems.